Patent US5019583A successfully refreshed from Google Patents.
US5019583A
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N-phenyl-N-(4-piperidinyl)amides useful as analgesics
Assignee: Mylan Teoranta
•
Filing: 1989-12-11
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Granted: 1991-05-28
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Expires: 2009-12-11
Abstract
Abstract N-Phenyl-N-(4-piperdinyl)amide derivatives are disclosed having the general formula (I): ##STR1## wherein X is a member selected from the group consisting of alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy-(C 1-2 )-alkoxy-carbonyl-lower alkyl, and Ar, R, R 1 and R 2 are defined hereinafter, including isomeric forms thereof and acid addition salts thereof. The compounds exhibit analgesic activity having relatively short durations of analgesic action. The invention embraces the compounds (I), pharmaceutical compositions of (I) and methods of providing analgesia with (I). Also included are certain novel intermediates for making (I).
Inventors
- 👤 Paul L. Feldman
- 👤 Michael K. James
- 👤 Marcus F. Brackeen
- 👤 Michael R. Johnson
- 👤 Harry J. Leighton
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-30 09:54
CPC Classifications
C; C07; C07D; C07D211/00; C07D211/04; C07D211/06; C07D211/08; C07D211/10; C07D211/14; C07D211/36; C07D211/56; C07D211/58; A; A61; A61P; A61P25/00; A61P25/04
Claims Analysis
Total Claims: 56
Claim 1
Independent Claim
133 words
A compound having the formula (I): ##STR15## wherein X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy-(C 1-2 )alkoxy-carbonyl-lower alkyl Ar is a member selected from the group consisting of phenyl and mono- di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and R 2 is a member selected from the group consisting of hydrogen and methyl; and the diastereomeric and enantiomeric isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers.
Claim 2
Dependent Claim
133 words
A compound having the formula (I): ##STR15## wherein X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy-(C 1-2 )alkoxy-carbonyl-lower alkyl Ar is a member selected from the group consisting of phenyl and mono- di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and R 2 is a member selected from the group consisting of hydrogen and methyl; and the diastereomeric and enantiomeric isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers.
Claim 3
Dependent Claim
10 words
The compound of claim 1 wherein X is alkoxy-carbonyl-lower alkyl.
Claim 4
Dependent Claim
11 words
The compound of claim 1 wherein X is lower alkyl-carbonyl-oxy-lower alkyl.
Claim 5
Dependent Claim
10 words
The compound of claim 1 wherein X is alkenyloxy-carbonyl-lower alkyl.
Claim 6
Dependent Claim
14 words
The compound of claim 1 wherein X is (C 1-2 )alkoxy-(C 1-2 )-alkoxy-carbonyl-lower alkyl.
Claim 7
Dependent Claim
11 words
The compound of claim 1 wherein Ar is phenyl or 2-fluorophenyl.
Claim 8
Dependent Claim
9 words
The compound of claim 1 wherein R is ethyl.
Claim 9
Dependent Claim
10 words
The compound of claim 1 wherein R 1 is methoxycarbonyl.
Claim 10
Dependent Claim
31 words
The compound of claim 1, wherein said compound is: 5-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]pentanoic acid, methyl ester; 2-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]ethyl acetate; 3-[4-[(1-oxopropyl)-2-fluorophenylamino]-1-piperidine]propanoic acid, methyl ester; or 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, vinyl ester, or pharmaceutically acceptable acid addition salt thereof.
Claim 11
Dependent Claim
12 words
3-[4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, alkyl ester, and the pharmaceutically acceptable acid addition salts thereof.
Claim 12
Dependent Claim
12 words
3-[4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, alkyl ester, and the pharmaceutically acceptable acid addition salts thereof.
Claim 13
Dependent Claim
28 words
The compound of claim 10, wherein in the alkyl portion of the said alkyl ester, the carbon directly attached to the oxygen is a methylene or methyl group.
Claim 14
Dependent Claim
19 words
The compound of claim 10, wherein said alkyl of said alkyl ester is of about 1 to 10 carbons.
Claim 15
Dependent Claim
13 words
The compound of claim 10, wherein said alkyl ester is the methyl ester.
Claim 16
Dependent Claim
12 words
A diastereomer or enantiomer of a compound as claimed in claim 1.
Claim 17
Dependent Claim
148 words
A pharmaceutical analgesic composition comprising an effective analgesic amount of a compound having the formula (I): ##STR16## wherein: X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy-(C 1-2 )alkoxy-carbonyl-lower alkyl; Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and R 2 is a member selected from the group consisting of hydrogen and methyl; and the diastereomeric and enantiomeric isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers; and a pharmaceutically acceptable carrier.
Claim 18
Dependent Claim
148 words
A pharmaceutical analgesic composition comprising an effective analgesic amount of a compound having the formula (I): ##STR16## wherein: X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy-(C 1-2 )alkoxy-carbonyl-lower alkyl; Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and R 2 is a member selected from the group consisting of hydrogen and methyl; and the diastereomeric and enantiomeric isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers; and a pharmaceutically acceptable carrier.
Claim 19
Dependent Claim
10 words
The composition of claim 15 wherein X is alkoxy-carbonyl-lower alkyl.
Claim 20
Dependent Claim
11 words
The composition of claim 15 wherein X is lower alkyl-carbonyloxy-lower alkyl.
Claim 21
Dependent Claim
10 words
The composition of claim 15 wherein X is alkenyloxy-carbonyl-lower alkyl.
Claim 22
Dependent Claim
14 words
The composition of claim 15 wherein X is (C 1-2 )alkoxy-(C 1-2 )-alkoxy-carbonyl-lower alkyl.
Claim 23
Dependent Claim
11 words
The composition of claim 15 wherein Ar is phenyl or 2-fluorophenyl.
Claim 24
Dependent Claim
9 words
The composition of claim 15 wherein R is ethyl.
Claim 25
Dependent Claim
10 words
The composition of claim 15 wherein R 1 is methoxycarbonyl.
Claim 26
Dependent Claim
31 words
The composition of claim 15 wherein said compound is: 5-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]pentanoic acid, methyl ester; 2-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]ethyl acetate; 3-[4-(1-oxopropyl)-2-fluorophenylamino]-1-piperidine]propanoic acid, methyl ester; 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, vinyl ester; or the pharmaceutically acceptable acid addition salt thereof.
Claim 27
Dependent Claim
12 words
3-[4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, alkyl ester, and the pharmaceutically acceptable acid addition salt thereof.
Claim 28
Dependent Claim
12 words
3-[4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, alkyl ester, and the pharmaceutically acceptable acid addition salt thereof.
Claim 29
Dependent Claim
28 words
The composition of claim 24 wherein in the alkyl portion of the said alkyl ester, the carbon directly attached to the oxygen is a methylene or methyl group.
Claim 30
Dependent Claim
19 words
The composition of claim 24, wherein said alkyl of said alkyl ester is of about 1 to 10 carbons.
Claim 31
Dependent Claim
13 words
The composition of claim 24, wherein said alkyl ester is the methyl ester.
Claim 32
Dependent Claim
13 words
The composition of claim 15, wherein said compound is a diastereomer or enantiomer.
Claim 33
Dependent Claim
15 words
The composition of claim 15, wherein said pharmaceutically acceptable carrier is suitable for parenteral administration.
Claim 34
Independent Claim
152 words
A method of providing analgesia in a mammal comprising administering to such mammal an analgesically effective amount of a compound having the formula (I): ##STR17## wherein: X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy-(C 1-2 )alkoxy-carbonyl-lower alkyl; Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxy-methyl; and R 2 is a member selected from the group consisting of hydrogen and methyl; and the optically active and cis-trans isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers.
Claim 35
Independent Claim
152 words
A method of providing analgesia in a mammal comprising administering to such mammal an analgesically effective amount of a compound having the formula (I): ##STR17## wherein: X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy-(C 1-2 )alkoxy-carbonyl-lower alkyl; Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxy-methyl; and R 2 is a member selected from the group consisting of hydrogen and methyl; and the optically active and cis-trans isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers.
Claim 36
Dependent Claim
10 words
The method of claim 30 wherein X is alkoxy-carbonyl-lower alkyl.
Claim 37
Dependent Claim
11 words
The method of claim 30 wherein X is lower alkyl-carbonyloxy-lower alkyl.
Claim 38
Dependent Claim
10 words
The method of claim 30 wherein X is alkenyloxy-carbonyl-lower alkyl.
Claim 39
Dependent Claim
14 words
The method of claim 30 wherein X is (C 1-2 )alkoxy-(C 1-2 )-alkoxy-carbonyl-lower alkyl.
Claim 40
Dependent Claim
11 words
The method of claim 30 wherein Ar is phenyl or 2-fluorophenyl.
Claim 41
Dependent Claim
9 words
The method of claim 30 wherein R is ethyl.
Claim 42
Dependent Claim
10 words
The method of claim 30 wherein R 1 is methoxycarbonyl.
Claim 43
Dependent Claim
32 words
The method of claim 30 wherein said compound is 5-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]pentanoic acid, methyl ester; 2-[4-methoxycarbonyl-4-(1-oxopropyl)phenylamino]-1-piperidine]ethyl acetate; 3-[4-[(1-oxopropyl)-2-fluorophenylamino]-1-piperidine]propanoic acid, methyl ester; or 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, vinyl ester; or a pharmaceutically acceptable acid addition salt thereof.
Claim 44
Dependent Claim
11 words
3-[4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, methyl ester, and the pharmaceutically acceptable acid addition salts
Claim 45
Dependent Claim
11 words
3-[4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, methyl ester, and the pharmaceutically acceptable acid addition salts
Claim 46
Dependent Claim
28 words
The method of claim 30, wherein in the alkyl portion of the said alkyl ester, the carbon directly attached to the oxygen is a methylene or methyl group.
Claim 47
Dependent Claim
19 words
The method of claim 30, wherein said alkyl of said alkyl ester is of about 1 to 10 carbons.
Claim 48
Dependent Claim
13 words
The method of claim 30, wherein said alkyl ester is the methyl ester.
Claim 49
Dependent Claim
13 words
The method of claim 30, wherein said compound is a diastereomer or enantiomer.
Claim 50
Dependent Claim
94 words
A compound having the formula (A): ##STR18## wherein: X a is carboxyloweralkyl; Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and R 2 is a member selected from the group consisting of hydrogen and methyl.
Claim 51
Dependent Claim
94 words
A compound having the formula (A): ##STR18## wherein: X a is carboxyloweralkyl; Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and R 2 is a member selected from the group consisting of hydrogen and methyl.
Claim 52
Dependent Claim
10 words
A compound of claim 44 wherein X a is carboxyethyl.
Claim 53
Dependent Claim
130 words
A compound having the formula (I): ##STR19## wherein: X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy-(C 1-2 )alkoxy-carbonyl-lower alkyl; Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and R 2 is a member selected from the group consisting hydrogen and methyl; and the diastereomeric and enantiomeric isomers thereof, and the acid addition salts of said compounds and isomers.
Claim 54
Dependent Claim
130 words
A compound having the formula (I): ##STR19## wherein: X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy-(C 1-2 )alkoxy-carbonyl-lower alkyl; Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and R 2 is a member selected from the group consisting hydrogen and methyl; and the diastereomeric and enantiomeric isomers thereof, and the acid addition salts of said compounds and isomers.
Claim 55
Dependent Claim
135 words
A compound having the formula: ##STR20## wherein: X is a member selected from the group consisting of: lower alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, lower alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy -(C 1-2 )alkoxy-carbonyl-lower alkyl; Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and R 2 is a member selected from the group consisting of hydrogen and methyl; and the diastereomeric and enantiomeric isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers.
Claim 56
Dependent Claim
135 words
A compound having the formula: ##STR20## wherein: X is a member selected from the group consisting of: lower alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, lower alkenyloxy-carbonyl-lower alkyl, and (C 1-2 )alkoxy -(C 1-2 )alkoxy-carbonyl-lower alkyl; Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl; R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl; R 1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and R 2 is a member selected from the group consisting of hydrogen and methyl; and the diastereomeric and enantiomeric isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers.
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